ABSTRACT

ImportanceTreatment of hepatitis C virus (HCV) infection in patients also infected with human immunodeficiency virus (HIV) has been limited due to drug interactions with antiretroviral therapies (ARTs) and the need to use interferon.

Design, Setting, and ParticipantsOpen-label, nonrandomized, uncontrolled phase 3 trial conducted at 34 treatment centers in the United States and Puerto Rico (August 2012-November 2013) evaluating treatment with sofosbuvir and ribavirin among patients with HCV genotypes 1, 2, or 3 and concurrent HIV. Patients were required to be receiving ART with HIV RNA values of 50 copies/mL or less and a CD4 T-cell count of more than 200 cells/μL or to have untreated HIV infection with a CD4 T-cell count of more than 500 cells/μL. Of the treatment-naive patients, 114 had HCV genotype 1 and 68 had HCV genotype 2 or 3, and 41 treatment experienced participants who had been treated with peginterferon-ribavirin had HCV genotype 2 or 3, for a total of 223 participants.

InterventionsTreatment-naive patients with HCV genotype 2 or 3 received 400 mg of sofosbuvir and weight-based ribavirin for 12 weeks and treatment-naive patients with HCV genotype 1 and treatment-experienced patients with HCV genotype 2 or 3 received the same treatment for 24 weeks.

Main Outcomes and MeasuresThe primary study outcome was the proportion of patients with SVR (serum HCV <25 copies/mL) 12 weeks (SVR12) after cessation of HCV therapy.

Conclusions and RelevanceIn this open-label, nonrandomized, uncontrolled study, patients with HIV who were coinfected with HCV genotype 1, 2, or 3 who received the oral, interferon-free combination of sofosbuvir and ribavirin for 12 or 24 weeks had high rates of SVR12. Further studies of this oral regimen in diverse populations of coinfected patients are warranted.

Figures in this Article

INTRODUCTION

Up to 7 million persons worldwide are infected with both human immunodeficiency virus (HIV) and hepatitis C virus (HCV).1 Human immunodeficiency virus and HCV coinfection is associated with high rates of liver fibrosis, cirrhosis, hepatocellular carcinoma, and overall mortality.2 Coinfected patients who are cured of HCV have improved clinical outcomes and survival.3

In treatment-naive patients coinfected with HCV and HIV, treatment for HCV genotypes 1, 2, or 3 infection has required 24 to 48 weeks of peglyated interferon and ribavirin with or without an HCV NS3/4A serine protease inhibitor, telaprevir or boceprevir, resulting in sustained virologic response (SVR) rates of 62% to 74%.4,5 However, the use of these regimens is limited due to complex dosing of the HCV NS3/4A protease inhibitors, poor tolerability, and drug interactions between HCV and antiretroviral drugs; moreover, up to 70% of patients with HIV/HCV coinfection are not eligible for HCV treatment regimens that include interferon.6,7 Sofosbuvir is an oral nucleotide analog HCV NS5B polymerase inhibitor recently approved for the treatment of HCV genotypes 1 through 4.8,9 Sofosbuvir has minimal or no drug interactions with a wide range of antiretroviral drugs.10 Phase 3 trials of sofosbuvir involving patients with HCV alone have demonstrated high rates of SVR when used in combination with ribavirin for 12 weeks for HCV genotype 2, or 12 to 24 weeks for HCV genotype 3, and in combination with peginterferon and ribavirin for 12 weeks for HCV genotypes 1, 4, 5, and 6.11- 13 The combination of sofosbuvir plus ribavirin for 24 weeks has also shown promise for patients with HCV genotype 1.14

We evaluated the rates of SVR and adverse events in patients infected with HIV and HCV genotype 1, 2, or 3 who were treated with the oral regimen of sofosbuvir and ribavirin for 12 or 24 weeks.

METHODS

Patients

We enrolled patients chronically infected with HCV at 34 academic, private practice, and community health centers in the United States and Puerto Rico from August 2012 through March 2013 (Study Protocol available in Supplement 1). Written informed consent was obtained from all patients prior to screening. To be eligible, patients had to be at least 18 years old, coinfected with HCV genotype 1, 2, or 3 and HIV, have a body mass index of 18 or more (calculated as weight in kilograms divided by height in meters squared). We enrolled patients with HCV genotype 1, 2, or 3 who had not received HCV treatment and patients with HCV genotype 2 or 3 who had been previously treated for HCV. Only patients with documentation indicating their cirrhosisis status were enrolled. Persons who inject drugs were not excluded by medical history alone; however, if they were actively using drugs they were excluded if they had a positive urine toxicology result at the screening visit. Patients receiving antiretroviral treatment (ART) were required to have been receiving a stable regimen for at least 8 weeks before screening, have an HIV RNA of less than 50 copies/mL and a CD4 T-lymphocyte count higher than 200 cells/μL. Antiretroviral regimens containing emtricitabine-tenofovir in combination with atazanavir-ritonavir, darunavir-ritonavir, efavirenz, raltegravir, or rilpivirine were included based on drug-interaction studies with sofosbuvir. Patients not receiving ART were required to have a CD4 T-lymphocyte count higher than 500 cells/μL at screening. No more than 20% of the entire study population was permitted to have evidence of cirrhosis at screening as assessed by a liver biopsy within 2 years of screening or by FibroSURE (Laboratory Corporation of America). Race was self-reported. Reasons for screen failure are reported in eTable 1 in Supplement 2.

Study Design

In this multicenter, open-label, nonrandomized, uncontrolled phase 3 trial,15 all patients received 400 mg of sofosbuvir (Gilead Sciences) administered orally once daily along with ribavirin (Ribasphere, Kadmon) administered orally twice daily, with doses determined according to body weight (1000 mg daily for patients with a body weight <75 kg and 1200 mg daily for patients with a body weight of ≥75 kg). The dose of ribavirin could be decreased or discontinued to help manage hemoglobin reductions according to the product label. The treatment duration was 12 weeks for treatment-naive patients with HCV genotype 2 or 3 and 24 weeks for treatment-naive patients with HCV genotype 1 and for treatment-experienced patients with HCV genotype 2 or 3.

Study Assessments

Serum HCV RNA was measured at screening and at every subsequent visit with the COBAS TaqMan HCV Test, version 2.0 for use with the High Pure System (Roche Molecular Systems) with a lower limit of quantification (LLOQ) of 25 IU/mL. Hepatitis C virus genotyping was determined with Siemens Versant HCV Genotype 2.0 assay. Human immunodeficiency virus RNA was measured at screening and at every subsequent visit using the AmpliPrep/COBAS TaqMan HIV test, version 2.0.

Hepatitis C viral relapse was defined as an HCV RNA level that was higher than the LLOQ at posttreatment weeks 4 or 12 after having an HCV RNA level that was lower than the LLOQ at the end of treatment. Hepatitis C viral breakthrough was defined as an HCV RNA level that was the LLOQ or higher during treatment after having previously had an HCV RNA level lower than the LLOQ while taking study drugs, confirmed with 2 consecutive values.

Other assessments conducted during the treatment phase were performed at 1- to 4-week intervals and included physical examination, review of medications, and safety assessments, including evaluations of renal function, hemoglobin levels, and liver function. Posttreatment assessments included safety assessments at the 4-week follow-up visit.

Plasma samples for HCV viral sequencing and possible phenotypic monitoring were collected at baseline (before treatment) and at every visit thereafter. We evaluated HCV NS5B gene nucleotide changes that may confer resistance to sofosbuvir at baseline and at the time of virologic relapse or breakthrough.

Statistical Analysis

The primary efficacy end point was SVR12, defined as an HCV RNA value that was less than the LLOQ 12 weeks after discontinuation of study drugs in all patients who were enrolled and who received study drugs.

For patients who were treatment naive, we planned to enroll approximately 115 patients with HCV genotype 1 and 55 with genotype 2 or 3. For patients who were previously treated for HCV, we planned to enroll 55 patients with genotype 2 or 3. No inferential statistics or statistical comparisons were planned for efficacy end points.

The point estimates for the SVR12 rate along with their 2-sided 95% exact confidence intervals (based on the Clopper-Pearson method) were provided for each treatment group. Exploratory multivariable logistic-regression analyses characterizing the relationship between the SVR12 rate and various prespecified demographic and baseline clinical characteristics were performed for each genotype group. A step-wise selection procedure was used to identify factors associated with SVR12 rates.

Study Oversight

This study was approved by the institutional review board or independent ethics committees at all participating sites and was conducted in compliance with the Declaration of Helsinki, Good Clinical Practice guidelines, and local regulatory requirements. An independent data and safety monitoring committee reviewed the progress of the study.

RESULTS

Baseline Characteristics

Overall, 330 patients coinfected with HIV and HCV were screened for the study, of whom 224 enrolled in the study and 223 began treatment (Figure 1 and eTable 1 in Supplement 2). The median number of patients at the 34 sites was 6, with a range of 1 to 17. The demographic and baseline clinical characteristics of the patients are shown in Table 1. Cirrhosis was more common in treatment-experienced patients and the median CD4 cell count was 562 to 581 cells/μL. In each treatment group, 90% to 98% of patients were taking ART. Of 11 patients not taking ART, 5 had an HIV RNA level that was less than 50 copies/mL at baseline. Among treatment-naive patients with genotype 1, the majority had subtype 1a and 32% were black.

Place holder to copy figure label and caption

Figure 1.

Flow Diagram of PHOTON-1 Patients

ART indicates antiretroviral therapy; HCV, hepatitis C virus; HIV, human immunodeficiency virus. aPatients could be excluded for more than 1 criterion. See eTable 12 in the Supplement. bPatient who did not receive the study treatment was not included in the efficacy analysis per protocol.

Response During and After Treatment

Patients treated with sofosbuvir plus ribavirin had a rapid decrease in levels of serum HCV. By treatment week 2, 75% of patients with HCV genotype 1, 91% of treatment-naive patients with HCV genotype 2 or 3, and 98% of treatment-experienced patients with HCV genotype 2 or 3 had HCV RNA levels lower than the LLOQ; by the fourth week of treatment, those proportions increased to 96% in the genotype 1, 99% in genotype 2 or 3, and 100% in treatment-experienced genotype 2 or 3 groups (Table 2). Two patients (1 each with genotype 1 and 2) experienced HCV virologic breakthrough; both had undetectable serum levels of sofosbuvir and its metabolite, GS-331007, at the time of HCV breakthrough, suggesting nonadherence to sofosbuvir.

The position of the solid squares indicates the rate of virologic response 12 weeks after the end of treatment for each subgroup; the horizontal lines indicate 95% confidence intervals. The vertical line represents the overall rate of sustained virologic response (SVR) for all patients with genotype 1. Body mass index is calculated as weight in kilograms divided by height in meters squared. ARV indicates antiretroviral therapy; NNRTI, nonnucleoside reverse transcriptase inhibitor; PI, protease inhibitor; SVR12, sustained virological response for 12 weeks; and ULN, upper limit of normal.

Of the 26 treatment-naive patients with HCV genotype 2 receiving 12 weeks of treatment, 23 (88%; 95% CI, 70%-98%) achieved SVR12. Of the 3 patients who did not, 1 patient had virologic breakthrough during the treatment phase for nonadherence and 2 patients could not be assessed because one patient withdrew consent and another was lost to follow-up. Of the 42 treatment-naive patients with HCV genotype 3 receiving 12 weeks of treatment, 28 (67%; 95% CI, 51%-80%) achieved SVR12. Among the 14 patients who did not, 12 experienced virologic relapse and 2 could not be assessed because one patient was lost to follow-up and another died after completing treatment. For subgroup rates for patients with HCV genotype 2, see eTable 4 in Supplement 2, and for patients with HCV genotype 3, see eTable 5 in Supplement 2.

Of the 24 treatment-experienced patients with HCV genotype 2 receiving 24 weeks of treatment, 22 (92%; 95% CI, 73%-99%) had achieved SVR12. One patient from this group withdrew consent and could not be assessed and another had virologic relapse. Notably, the latter patient only received 8 weeks of study treatment and was found to have discordant NS5B sequencing from screening HCV genotyping (genotype 1 by sequencing and genotype 2 by the screening INNO-LiPA), which may represent a chimeric virus. Two other patients with discordant NS5B sequencing and INNO-LiPA analysis in this group completed 24 weeks of treatment and achieved SVR12. Of the 17 treatment-experienced patients with HCV genotype 3, 16 (94%; 95% CI, 71%-100%) achieved SVR12, with 1 patient having viral relapse at the 12-week SVR assessment. Among both treatment-naive and treatment-experienced patients with HCV genotype 2, an exploratory multivariable analysis demonstrated only study drug completion to be associated with SVR (OR, 200; 95% CI, 4->1000; P = .002: eTable 6 in Supplement 2). Among both treatment-naive and treatment-experienced patients with HCV genotype 3, no baseline factors were associated with SVR12 by exploratory multivariable analysis, although treatment-experienced patients assigned to the 24-week treatment group had numerically higher SVR12 rates (OR, 8; 95% CI, 0.96-66.6; P = .06: eTable 7 in Supplement 2).

Viral Resistance Testing

Baseline population sequencing was performed in 219 patients. No S282T mutation was detected in any patient at baseline. The L159F mutation was detected in 2 patients with one patient achieving SVR12 and the other experiencing viral relapse. No baseline V321A mutations were identified. An NS5B deep sequencing (1% detection threshold) was performed for 30 patients at baseline and at the time of virologic breakthrough (n = 2) or relapse (n = 28).

In the 2 patients with HCV virologic breakthrough, deep sequencing did not demonstrate S282T, L159F, or V321A NS5B mutations. Deep sequencing for the 28 patients with viral relapse (1% detection threshold) demonstrated no evidence of the S282T or V321A mutations. The L159F mutation emerged in 4 patients (2 genotype 3a patients at 1.1% and 1.2%; 1 genotype 1a patient at >99%; and 1 genotype 1b patient at >99%), but did not confer phenotypic shift to sofosbuvir resistance in vitro.

Safety

Of the 223 patients who received at least 1 dose of the study drug, 7 (3%) discontinued treatment due to an adverse event (Table 3 and eTable 8 in Supplement 2). Serious adverse events were experienced by 14 patients (6%) (eTable 9 in Supplement 2). The incidence of serious adverse events and adverse events leading to discontinuation was similar in the 12- and 24-week groups. One death occurred: a patient with HCV genotype 3 committed suicide 9 days after completing 12 weeks of treatment per protocol.

Most adverse events were grade 1 or 2 in severity with the most common adverse events in all treatment groups being fatigue, insomnia, nausea, and headache. The most common laboratory abnormalities included anemia and elevations in indirect bilirubin. Thirty-four patients (15%) had decreases in hemoglobin to lower than 10 mg/dL with 3 patients experiencing decreases in hemoglobin to less than 8.5 mg/dL. Forty-three patients (19% of total participants) required dose reduction of ribavirin; the use of erythropoietin was prohibited in this study (Table 3). Overall, 32 patients (14%) experienced elevations of total bilirubin to higher than 3.0 mg/dL (to convert bilirubin from mg/dL to μmol/L, multiply by 17.104). Consistent with ribavirin-associated hemolysis, the maximum increase was observed during the first 2 weeks of treatment with sofosbuvir plus ribavirin and no patient had a grade 3 or 4 increase in direct bilirubin levels. Thirty (94%) of 32 of these patients were taking ritonavir-boosted atazanavir as part of the baseline ART regimen (Table 3). Four patients changed ART regimens from atazanavir to darunavir due to increased indirect bilirubin during the study with all patients having normalization of total bilirubin levels following the change in ART (eTable 10 in Supplement 2). All patients with elevations in total bilirubin had a return to baseline levels by the posttreatment week 12 evaluation.

There were no clinically significant changes in HIV RNA levels in those patients not receiving ART at baseline (eTable 11 in Supplement 2). Of patients taking ART with suppressed HIV viremia upon entering the study, 2 experienced HIV viral breakthrough. One of these patients had increases in HIV RNA levels due to documented nonadherence to ART and the other resuppressed the HIV RNA without changes to the ART regimen.

Consistent with the known lymphopenic effect of ribavirin, there was a decrease in absolute lymphocyte counts and absolute CD4 T-cell counts during study treatment.16 The CD4 T-cell percentage did not change throughout study treatment (eTable 12 in Supplement 2). Absolute CD4 T-cell counts returned to baseline by posttreatment week 12 assessments (eTable 12 in Supplement 2).

DISCUSSION

In this open-label, nonrandomized, uncontrolled study, patients with HIV who were coinfected with HCV genotype 1, 2, or 3 who received the oral, interferon-free combination of sofosbuvir and ribavirin for 12 or 24 weeks had high rates of SVR12.

For patients coinfected with HCV genotype 1, the SVR rate of 76% following 24 weeks of sofosbuvir plus ribavirin was similar to results observed in coinfected patients in smaller, phase 2 studies of 48 weeks of treatment with an HCV protease inhibitor plus peginterferon and ribavirin4,5 and to results observed in a smaller study of 24 weeks of sofosbuvir plus ribavirin in HCV monoinfected patients.14 In our coinfected patient population, patients with HCV genotype 1 and characteristics that have historically been considered difficult to cure had high rates of SVR12 following receipt of the 24-week treatment regimen of sofosbuvir and ribavirin. By exploratory multivariable analysis, the strongest factor associated with SVR12 was completion of the treatment regimen. Patients infected with HCV genotype 1a had a higher rate of SVR12 than did those infected with HCV genotype 1b. This finding may be explained by the small number of patients with genotype 1b infection or by confounding factors such as black race, which were more common in persons infected with genotype 1b than in those infected with genotype 1a. Overall, the observed HCV responses in patients with HIV-HCV coinfection were consistent with those previously reported in patients with HCV monoinfection. Furthermore, because sofosbuvir and its metabolites do not have significant interactions with the cytochrome P450 system, sofosbuvir plus ribavirin could be coadministered with a wide range of antiretroviral drugs including those that induce (eg, efavirenz) or inhibit (eg, ritonavir) or are metabolized by (eg, darunavir; atazanavir) these enzymes. Importantly, more than one-quarter of patients coinfected with HIV and HCV treated with sofosbuvir plus ribavirin were not eligible for interferon-containing HCV treatment regimens due to contraindications to its use. Among treatment-naive and previously treated patients with HCV genotype 2, high rates of SVR12 were observed with both the 12- and 24-week regimens. Among patients with HCV genotype 3, there was a substantially higher rate of SVR12 in treatment-experienced patients treated for 24 weeks with sofosbuvir and ribavirin (94%) than in those treated for 12 weeks (67%). This observation is consistent with the results of the VALENCE13 study, which demonstrated higher rates of SVR12 in HCV genotype 3 monoinfected patients treated for 24 weeks than for those treated for 12 or 16 weeks in other studies. These data suggest that the sofosbuvir and ribavirin treatment durations for HIV-infected patients with HCV genotype 2 or 3 infection should mirror those established for HCV monoinfected patients, namely, 12 and 24 weeks for HCV genotypes 2 and 3, respectively.

No S282T mutations were detected in patients with viral relapse or breakthrough, confirming the high barrier to resistance demonstrated in other studies of sofosbuvir.11,12 In vitro analyses identified no other mutations that conferred phenotypic resistance to sofosbuvir.

Rates of premature discontinuation of study drug were low in both 12- and 24-week regimens (3%-4%), rates lower than those observed in the phase 2 studies of HCV protease inhibitors (8%-20%), but were somewhat higher than those observed in phase 3 studies of sofosbuvir and ribavirin in HCV monoinfected patients.4,5,11,12 The most common adverse events were mild to moderate in severity and included fatigue, insomnia, nausea, and headache. No serious adverse events related to the study drugs were observed. Laboratory abnormalities were consistent with known effects of ribavirin therapy, including decreases in hemoglobin and absolute CD4 T-cell counts. Among patients taking ritonavir-boosted atazanavir, increases in indirect bilirubin were observed, typically early in the course of therapy. This finding is consistent with the ribavirin-induced hemolysis in the setting of UGT1A1 inhibition by atazanavir, which has been previously reported.5,17,18 Although this increase was not associated with elevations in serum liver enzyme levels or other markers of liver injury, 4 patients elected to switch to another boosted HIV protease inhibitor with normalization of total bilirubin. For all patients with elevations in indirect bilirubin, levels returned to baseline after ribavirin treatment was completed.

No other untoward effects of sofosbuvir and ribavirin on HIV disease or its treatment with antiretrovirals were detected. Among patients not taking antiretroviral therapy at entry, no HIV-specific antiviral effect of sofosbuvir was observed, consistent with in vitro data.8 Among those taking antiretroviral therapy, 2 patients experienced HIV virologic rebound, but both were documented to be poorly adherent to ART.

This study has several limitations. First, patients with cirrhosis (10%) and women (17%) were underrepresented. In addition, relatively few patients with advanced HIV disease (AIDS or low CD4 cell count) were enrolled; as such, the safety, tolerability, and efficacy of sofosbuvir plus ribavirin among such patients is not known and additional studies are warranted. Furthermore, the absence of a control group limits the ability to derive definitive conclusions regarding the safety and efficacy of this regimen. Lastly, sofosbuvir was not studied in combination with other anti-HCV therapies such as peginterferon alfa or other HCV direct-acting antivirals. The combination of sofosbuvir, ribavirin, and peginterferon has been studied in 23 HIV-HCV coinfected patients receiving concurrent antiretroviral therapy, of whom, 21 achieved SVR12.19 In addition, studies of sofosbuvir in combination with ledipasivir, an inhibitor of HCV NS5A, are under way in patients coinfected with HIV and HCV (ClinicalTrials.gov identifier: NCT02073656).

CONCLUSIONS

In this open-label, nonrandomized, uncontrolled study, HIV-infected patients with HCV genotypes 1, 2, or 3 coinfection who received an oral combination of sofosbuvir plus ribavirin for 12 or 24 weeks had high rates of sustained HCV virologic response 12 weeks after cessation of therapy. Further studies of this regimen in more diverse populations of coinfected patients are needed.

Role of the Sponsors: Gilead (the sponsor) provided the study drug. In collaboration with the principal investigator (M.S.S.) and the publication committee (S.N., M.R.T., D.D.), the sponsor designed and conducted the study, collected the data, monitored the conduct of the study, and performed the statistical analyses. The interpretation of the data was performed by the sponsor in concert with the principal investigators and the publication committee. The first draft of the manuscript and all subsequent drafts was prepared by the academic and industry authors, with assistance from a medical writer employed by the sponsor. The decision to submit the manuscript for publication was the responsibility of the principal investigator, the publication committee, and the sponsor. The academic authors vouch for the completeness and accuracy of the data and data analyses and for the fidelity of the study to the protocol.

Previous Presentations: Presented in part at the 64th annual meeting of the American Association for the Study of Liver Diseases; November 1-5, 2013; Washington, DC; and at the Conference on Retroviruses and Opportunistic Infections (CROI); March 3-6, 2014; Boston, Massachusetts.

Additional Contributions: We thank Maryanne Lenoci and Sherri Paxton of Gilead Sciences for providing clinical operations support and David McNeel, MA, and Kellie Chu of Gilead Sciences for providing editorial support. These persons received no compensation apart from usual salary for their contributions.

Correction: This article was corrected on July 23, 2014, to fix incorrect information in the text, in the Figure, and in Tables 1 and 3.

American Association for the Study of Liver Diseases and the Infectious Diseases Society of America. Recommendations for testing, managing, and treating hepatitis C.www.hcvguidelines.org. Accessed May 30, 2014.

Figures

Place holder to copy figure label and caption

Figure 1.

Flow Diagram of PHOTON-1 Patients

ART indicates antiretroviral therapy; HCV, hepatitis C virus; HIV, human immunodeficiency virus. aPatients could be excluded for more than 1 criterion. See eTable 12 in the Supplement. bPatient who did not receive the study treatment was not included in the efficacy analysis per protocol.

The position of the solid squares indicates the rate of virologic response 12 weeks after the end of treatment for each subgroup; the horizontal lines indicate 95% confidence intervals. The vertical line represents the overall rate of sustained virologic response (SVR) for all patients with genotype 1. Body mass index is calculated as weight in kilograms divided by height in meters squared. ARV indicates antiretroviral therapy; NNRTI, nonnucleoside reverse transcriptase inhibitor; PI, protease inhibitor; SVR12, sustained virological response for 12 weeks; and ULN, upper limit of normal.

American Association for the Study of Liver Diseases and the Infectious Diseases Society of America. Recommendations for testing, managing, and treating hepatitis C.www.hcvguidelines.org. Accessed May 30, 2014.

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